This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project focuses on understanding the reasons why natural hosts for SIV infection, such as the sooty mangabeys (SMs), in striking contrast to HIV-infected individuals, are not susceptible to AIDS despite high viremia. We recently showed that CCR5 expression is significantly lower in central memory CD4+ T cells of SMs when compared to humans and macaques, and that this lower expression results in decreased susceptibility to SIV infection. This work is now submitted for publication. In addition, as part of the studies sponsored by R01-AI66998, we have made three novel observation that are all now published (see below). The first observation is that the conclusion of a five-years longitudinal survey of naturally SIV-infected SMs prompted us to realize that the infection is associated with a slow but progressive decline of CD4+ T cells without increasing viral load or immune activation. The second observation is that 5-7% of naturally SIV-infected SMs are homozygous for a 2bp deletion in the second extracellular loop of CCR5 that results in abrogated surface expression of thsi molecule. Interestingly, these rare CCR5 knock-out SMs are infected with SIV albeit at lower levels. These animals do not develop viruses using CXCR4, but other SIV co-receptors such as GPR-1 and GPR-15. The third observation is that, in naturally SIV-infected SMs, the level of autologous neutralizing antibodies is very low, and does not correlate with either viral load or CD4+ T cell loss. We believe that these data improve our understanding of the pathophysiology of SIV infection in SMs.